Cancer cells gain growth advantages in the microenvironment by shifting cellular metabolism from oxidative phosphorylation to glycolysis, the so-called Warburg effect. This glycolytic shift enables cancer cells to adapt to low-oxygen microenvironments, to generate biosynthetic building blocks for cell proliferation, to acidify the local environment to facilitate tumor invasion, and to generate NADPH and glutathione through pentose phosphate shunt to increase resistance to oxidative stress. Kroemer, G.; Pouyssegur, J., Cancer Cell, 13, 472-82 (2008). Thus, the Warburg effect is considered as a fundamental property of neoplasia, thereby constituting the basis for tumor imaging by [18F]2-fluoro-2-deoxyglucose positron emission tomography.
From a therapeutic perspective, targeting glycolysis by blocking glucose uptake represents a clinically relevant strategy for cancer treatment, which has constituted the focus of many investigations. To date, a number of small-molecule agents with the capability to suppress the activity/expression of glucose transporters have been reported, including resveratrol (Park, J. B. J Nat Prod, 64, 381-4 (2001)), naringenin (Harmon et al., Breast Cancer Res Treat, 85, 103-10 (2004)), phloretin (Cao et al., Cancer Chemother Pharmacol, 59, 495-505 (2007)), fasentin (Wood et al., Mol Cancer Ther, 7, 3546-55 (2008)), 8-aminoadenosine (Shamnugam et al., J Biol Chem, 284, 26816-30 (2009)), and STF-31.13. Exposure of cancer cells to these agents gave rise to reduced cell proliferation and/or chemosensitization, providing a proof-of-concept that targeting glucose transporters represents a therapeutically relevant strategy for cancer treatment.
It has previously been demonstrated that the suppressive effects of the peroxisome proliferator-activated receptor (PPAR)γ agonist ciglitazone (1), shown in FIG. 1, on various signaling pathways, including those mediated by cyclin D1, Sp1, and androgen receptor (AR), in prostate cancer cells was attributable to its ability to block glucose entry independently of PPARγ. Wei et al., J Biol Chem, 285, 9780-91 (2010); Wei et al., Mol Pharmacol, 76, 47-57 (2009).
The pharmacological exploitation of the PPARγ-inactive analogue of compound 1, (Z)-5-(4-[(1-methylcyclohexyl)methoxy]benzylidene)-thiazolidine-2,4-dione (Δ2CG, 2), as a scaffold to develop androgen receptor (AR)-ablative agents via its permuted isomer 3 has been reported, which led to (Z)-5-(4-hydroxy-3-(trifluoromethyl)benzylidene)-3-((1-methylcyclohexyl) methyl)thiazolidine-2,4-dione (CG-12, 4) as the optimal compound (FIG. 1A). Yang et al., J Med Chem, 51, 2100-7 (2008). However, there remains a need for new energy restriction mimetic agents, particularly those exhibiting increased potencies.